Advances in our understanding of the molecular mechanisms underlying various genetic arrhythmia syndromes bring the promise of many new and better treatments. Despite this promise, current treatment is based on empiric observations, retrospective data, and small case series. The research we propose addresses this disparity by translating discovery in cellular and animal models to prospective trials in genetic arrhythmia syndromes. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic syndrome characterized by frequent ventricular tachycardia and risk for sudden death. Although the genetic and molecular basis of the disease is now understood, current drug treatment strategies remain essentially unchanged since the initial description of the syndrome >30 years ago. We recently discovered that the antiarrhythmic drug flecainide directly targets the molecular defect in CPVT. We tested flecainide in our mouse model of CPVT and found that it completely eliminated VT. We then performed an international multicenter trial of flecainide in CPVT patients with persistent exercise-induced VT despite maximally-tolerated standard therapy. Flecainide significantly reduced or eliminated VT in the majority of these patients. Thus, flecainide is a promising candidate to translate basic discovery into better treatments for genetic arrhythmia syndromes. To date, the effectiveness of flecainide in improving the clinical outcome of CPVT patients has not been tested. This is a critical issue, as flecainide increases mortality in patients after myocardial infarction despite a strong suppression of ventricular ectopy. In this proposal, we will test the hypothesis that flecainide will reduce cardiac events in patients with CPVT. We will also seek to identify novel genetic causes and genetic modifiers of CPVT with next-generation sequencing of candidate genes in subjects enrolled in the trial. Accomplishing these specific aims will result in a radical shift in genetic arrhythmia syndrome research including mechanism- based and personalized treatments and prospective trials with hard endpoints. PUBLIC HEALTH RELEVANCE: The proposed research will study a promising new treatment for a deadly heart rhythm disease, while studying how a person's genes affect that disease. This research has potential to identify new life-saving treatments for this disease, help scientists learn more about the disease, and provides a new model to do this in many other diseases, thereby significantly impacting public health.